AUTOIMMUNITY AND THE MUSCULOSKELETAL SYSTEM

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AUTOIMMUNITY AND THE MUSCULOSKELETAL SYSTEM



Nicholas Manolios




Chapter objectives


After studying this chapter you should be able to:




Introduction


Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease, characterized by excessive auto-antibody production, immune complex formation andimmunologically-mediated tissue injury at multiple sites. It is a clinically heterogeneous disorder with a broad spectrum of presentations. Although the immune mechanism/s responsible for the breakdown of tolerance against self-antigens is unknown, a genetic influence in disease predisposition has been clearly demonstrated. Like most other connective tissue disorders, auto-antibody testing can be of value in making the diagnosis. These results must always be correlated with the patient’s symptoms and signs for correct interpretation. Treatment is symptomatic and aimed at suppressing an altered immune system that causes end-organ damage. In Chapter 1 we dealt with another autoimmune disease—rheumatoid arthritis. This chapter will be illustrated by a case of SLE that tracks its course over several years to illustrate its clinical and immunological features.



Interesting facts


Lupus with its characteristic butterfly rash was long considered a skin disease. Kaposi in 1870 recognized that lupus had other extra-cutaneous manifestations such as arthritis and at the turn of the century, Osler recognized the systemic nature of the disease. In the 1920s Libman and Sacks differentiated the effects of lupus on the heart from that of rheumatic fever and, in 1938, Hargraves noted the LE-cell phenomenon, which later became the test for lupus. Steroids revolutionized the treatment of lupus in the 1950s; anti-nuclear antibodies were introduced for the identification and diagnosis of lupus in the 1960s. The survival of lupus patients has dramatically increased over the last 50 years. In 1953, 4 years after diagnosis 50% of patients had died. Nowadays, the majority of cases can be controlled with proper treatment.



Immunology



Autoimmunity


Despite the heterogeneity of clinical features of SLE discussed later in this chapter, one characteristic laboratory finding is the presence of antibodies generated by the person’s own immune system against a wide range of ‘self’ antigens, such as deoxyribonucleic acids (DNA) and ribonucleoproteins. Since these antibodies are directed against ‘self’ antigens they are called ‘autoantibodies’. A schematic representation of an antigen–antibody (immune) complex is shown in Figure 9.1. The exact reason for this breakdown of immune tolerance is still unclear. The consequence of immune complex deposition in many vascular beds throughout the body results in a wide variety of clinical presentations. These manifestations are dictated by the site and extent of the inflammatory process, triggered by the antibody–antigen complex.




Case 9.1   SLE: 1



Case history


Melanie, an 18-year-old woman initially presented to her GP complaining of joint pain in both hands. On specific questioning it was noted that she had felt unwell over the preceding several months and was experiencing increasing lethargy which was disproportionate to her daily activities. Other features noted in her history were the presence of facial rash, alopecia (hair loss) and mouth ulcers. There was no history of drug ingestion, overseas travel, diarrhoea, urinary tract symptoms or recent upper respiratory infection. The patient had a twin sister and two other siblings who were well. There was no family history of arthritis.


Physical examination revealed an ill-looking woman with a malar rash in a butterfly distribution over the face. The hair was sparse and there were mouth ulcers in the buccal cavity. Examination of the musculoskeletal system revealed tenderness in the proximal interphalangeal and metacarpophalangeal joints of both hands consistent with a symmetrical polyarthritis. There were small effusions present in both knees. There were no nodules or psoriatic skin changes. Heart sounds were dual with no murmurs and breath sounds were normal.


A presumptive diagnosis of SLE was made. To confirm the clinical suspicion and to assess the extent of disease activity, she underwent a variety of serum and urine tests including testing for various autoantibodies. The serum tests showed a mild anaemia, elevated ESR, a positive antinuclear antibody (ANA) at a titre of 1:640 with a homogeneous pattern and positive antibody to the Sm antigen. Biochemistry and urinalysis were normal. The patient was started on prednisone and hydroxychloroquine.



Immunopathology


An autoimmune disease like SLE is characterized by the production of many autoantibodies. Their exact role in disease aetiopathogenesis remains unclear. Some auto-antibodies have been shown to contribute directly to the clinical picture by causing cell death. For example, anti-erythrocyte antibodies result in haemolysis (red cell lysis) and lymphocytotoxic antibodies are responsible for the reduced lymphocyte count (lymphopenia) that occurs in active lupus. An alternative mechanism of tissue injury is deposition of antigen–antibody complexes with complement activation. This is seen particularly in the kidney and skin. Complement and pro-inflammatory cytokine production result in polymorph trafficking into the area in question. Further release of pro-inflammatory mediators from mast cells, basophils and polymorphs perpetuate the inflammatory cascade. Platelet aggregation and clot formation result in microthrombi formation and tissue ischaemia. This is compounded by the release of proteases, hydrolytic enzymes and free radicals. Complement activation may also lead both directly (via complement components C5–9) and indirectly to cell lysis. Resultant end-organ damage in various tissues such as the kidney, skin and brain are responsible for the clinical manifestations of the disease. Under normal circumstances, antigen–antibody complexes are rapidly and efficiently cleared by phagocytes. However, defective mechanisms of immune complex clearance may perpetuate the inflammatory response.


Complement receptors (CR) bind different complement fragments produced during complement activation. They are found on erythrocytes (CR1), B cells (CR2), macrophages and polymorphonuclear cells (CR3, CR4). Deficiency in these receptors may lead to continued inflammation and immune complex deposition. Immune complexes may also be cleared via the immunoglobulin portion of Fc receptors expressed on monocytes, polymorphonuclear cells and other immune cells. The Fc receptors are encoded by genes on chromosome 1 and have different forms (alleles) that may influence immune complex handling.






Serological manifestations of autoimmunity





Antinuclear antibodies


The most typical serologic abnormality in SLE is the presence of ANA antibodies. These antibodies are usually directed against intra-nuclear proteins involved in DNA packaging, RNA splicing or RNA translation. The two important features of an ANA are: (1) the titre (extent of serum dilution that still gives a detectable pattern) and (2) the pattern of immunofluorescence.




Staining patterns

Different staining patterns (Fig. 9.2) reflect the nature of the antigen and its distribution. Their disease associations are summarized in Table 9.1. Different patterns include:








Anti-centromere pattern

This specific speckled pattern is due to antibodies to the centromere and results in exactly 46 nuclear speckles. Anti-centromere antibodies are associated with the CREST syndrome, a limited variant of the disease scleroderma. The latter is also known as systemic sclerosis. CREST comprises C for calcinosis (calcium hydroxyapatite deposition in soft tissues), R for Raynaud’s phenomenon (abnormal vascular sensitivity of the digits on exposure to cold, characterized by a classical three-phase colour change of white, then blue, then red), E for esophageal dysfunction (usually manifest initially as difficulty swallowing), S for sclerodactyly (thickening of the skin of the digits) and T for telangiectasia (localized capillary dilatation and tortuosity in the skin). Anti-centromere antibody is uncommon in the more diffuse form of systemic sclerosis and is only rarely found in other connective tissue disorders.





Antibodies to dsDNA


Antibodies to double-stranded DNA (dsDNA) are specific for SLE, being present in 40% of patients. Elevated levels are usually associated with active disease, but patients can have elevated DNA antibodies and be clinically quiescent. Rapid rises or falls in DNA antibody levels with doubling or halving time of 4 weeks or less, may precede flares in the disease. Levels may fall with successful treatment. The presence of dsDNA correlates well with the probability of development of lupus nephritis (kidney disease). Many normal people have IgM antibodies to single-stranded DNA (ssDNA). However, IgG antibodies to dsDNA are less prevalent in normal controls and are highly suggestive of SLE. They have a pathogenic role by complexing with DNA trapped in glomeruli or by direct attachment to glomerular structures. Their complement-fixing ability then results in tissue damage.


Serum complement levels of C3 and C4 are useful in monitoring disease activity in conjunction with dsDNA levels. A rapid rise or fall of dsDNA levels in association with a fall in complement C3 and/or C4, is more likely to be significant than when the complement levels remain normal.



Antibodies to extractable nuclear antigens


The extractable nuclear antigens (ENA) consist of a number of antigens which include ribonucleoprotein (RNP), Smith antigen (Sm), SS-A/Ro, SS-B/La, Jo-1, ribosomal-p, and Scl-70. Their disease associations are summarized in Table 9.2. Autoantibodies can also be useful in helping with the diagnosis of connective tissue disorders (Table 9.2). The clinical findings are the most important factor in determining which autoantibody to measure.







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Jul 3, 2016 | Posted by in MUSCULOSKELETAL MEDICINE | Comments Off on AUTOIMMUNITY AND THE MUSCULOSKELETAL SYSTEM

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